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Because the nervous system develops from the epithelial layer of the embryo, a number of congenital diseases include both neurologic and cutaneous manifestations. Among these disorders, three are discussed below, and von Hippel-Lindau disease is discussed in Chapter 26.
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1. TUBEROUS SCLEROSIS
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Tuberous sclerosis may occur sporadically or on a familial basis with autosomal dominant inheritance. The disease is caused by mutations that inactivate either the TSC1 (hamartin) gene on chromosome 9 or the TSC2 (tuberin) gene on chromosome 16, resulting in constitutive expression of mTOR (mammalian target of rapamycin) and impaired tumor suppression in multiple tissues. Neurologic presentation is with seizures and progressive psychomotor delay beginning in early childhood. The cutaneous abnormality adenoma sebaceum becomes manifest usually between 5 and 10 years of age and typically consists of reddened nodules on the face (cheeks, nasolabial folds, sides of the nose, and chin) and sometimes on the forehead and neck. Other typical cutaneous lesions include subungual fibromas, shagreen patches (leathery plaques of subepidermal fibrosis, situated usually on the trunk), and leaf-shaped hypopigmented spots. Associated abnormalities include retinal lesions and tumors, benign rhabdomyomas of the heart, lung cysts, benign tumors in the viscera, and bone cysts.
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The disease is slowly progressive and leads to increasing mental deterioration. Anticonvulsants are indicated to control seizures. Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, is approved in the United States and Europe for medically refractory epilepsy and subependymal giant cell astrocytomas due to tuberous sclerosis.
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Neurofibromatosis may occur either sporadically or on a familial basis with autosomal dominant inheritance. Two distinct forms are recognized: Type 1 (Recklinghausen disease) is characterized by multiple hyperpigmented macules, Lisch nodules, and neurofibromas, and results from mutations in the NF1 gene on chromosome 17. Type 2 is characterized by bilateral eighth nerve tumors, often accompanied by other intracranial or intraspinal tumors, and is associated with mutations in the NF2 (merlin) gene on chromosome 22.
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Neurologic presentation is usually with symptoms and signs of tumor. Multiple neurofibromas characteristically are present and may involve spinal or cranial nerves, especially the eighth nerve (eFigures 24–8, 24–9, and 24–10). Examination of the superficial cutaneous nerves usually reveals palpable mobile nodules. In some cases, there is marked overgrowth of subcutaneous tissues (plexiform neuromas), sometimes with an underlying bony abnormality. Associated cutaneous lesions include axillary freckling and patches of cutaneous pigmentation (café au lait spots) (eFigures 24–11 and 24–12). Malignant degeneration of neurofibromas occasionally occurs and may lead to peripheral sarcomas. Meningiomas, gliomas (especially optic nerve gliomas), bone cysts, pheochromocytomas, scoliosis, and obstructive hydrocephalus may also occur. Selumetinib (25 mg/m2 orally twice daily), a mitogen-activated protein kinase inhibitor, causes plexiform neurofibromas to shrink by at least 20% in two-thirds of patients and is approved by the FDA for treatment of inoperable plexiform neurofibromas in children 2 years ...